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2012 120: 538-551

doi:10.1182/blood-2012-01-380139 originally published
online May 30, 2012

How I treat prolymphocytic leukemia

Claire Dearden

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How I treat

How I treat prolymphocytic leukemia

Claire Dearden1
1Department

of Haemato-Oncology, Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom

T- and B-cell subtypes of prolymphocytic

leukemia (PLL) are rare, aggressive lymphoid malignancies with characteristic
morphologic, immunophenotypic, cytogenetic, and molecular features. Recent
studies have highlighted the role of specific oncogenes, such as TCL-1, MTCP-1,
and ATM in the case of T-cell and TP53
mutations in the case of B-cell prolymphocytic leukemia. Despite the advances in
the understanding of the biology of these
conditions, the prognosis for these patients remains poor with short survival

and no curative therapy. The advent of

monoclonal antibodies has improved
treatment options. Currently, the best
treatment for T-PLL is intravenous alemtuzumab, which has resulted in very high
response rates of more than 90% when
given as first-line treatment and a significant improvement in survival. Consolidation of remissions with autologous or
allogeneic stem cell transplantation
further prolongs survival, and the latter
may offer potential cure. In B-PLL,
rituximab-based combination chemo-

immunotherapy is effective in fitter patients. TP53 abnormalities are common

and, as for chronic lymphocytic leukemia,
these patients should be managed using
an alemtuzumab-based therapy. The role
of allogeneic transplant with nonmyeloablative conditioning needs to be explored
further in both T- and B-cell PLL to
broaden the patient eligibility for what
may be a curative treatment. (Blood. 2012;
120(3):538-551)

Introduction
Prolymphocytic leukemias (PLLs), first described in the 1970s, are
rare mature lymphoid disorders of B- and T-cell subtypes with
distinct features and an aggressive clinical course.1-3 Relevant
oncogenes, such as T-cell leukemia-1 gene (TCL-1) and ataxia
telangiectasia-mutated gene (ATM) in the case of T-PLL, and TP53
in B-PLL have been identified and shown to play a role in the
pathogenesis of these disorders. Despite advances in understanding
of the biology and pathogenesis, the prognosis for this group
remains poor with early relapse and short overall survival (OS).
The use of the monoclonal anti-CD52 antibody, alemtuzumab, has
improved the outcome and survival in T-PLL, allowing for
high-dose therapy options aimed at eradicating the disease. In
B-PLL, the approach to treatment is similar to that used in chronic
lymphocytic leukemia (CLL). Because of the distinct pathologic
features and different therapeutic strategies for B- and T-cell PLL,
I discuss them separately.

T-PLL
T-PLL is a rare mature postthymic T-cell neoplasm. In our
experience, it accounts for up to one-third of mature T-cell
malignancies with a leukemic presentation, but these account for
only a very small percentage of all lymphoid malignancies.
Clinicians will often only see a case of T-PLL once every 5 to
10 years, which makes recognition of the disorder difficult. The
necessary starting point, therefore, before addressing the question
of treatment, is to discuss the clinical presentation, the importance
of selecting the appropriate diagnostic tests, and the interpretation
of test results to arrive at a correct diagnosis. This is essential
because the treatment approach is tailored to T-PLL very specifically and would not be that adopted for other T-cell malignancies.

Submitted January 21, 2012; accepted May 14, 2012. Prepublished online as
Blood First Edition paper, May 30, 2012; DOI 10.1182/blood-2012-01-380139.

538

Patients are sometimes incorrectly diagnosed and have poor

outcomes as a result.
Recognizing the clinical features

T-PLL typically follows an aggressive clinical course from

presentation (Table 1). A minority of patients ( 15%) may be
asymptomatic at diagnosis, and this indolent phase can persist
for a variable length of time, which may extend to several
years.4 However, progression is inevitable and may be very
rapid when it occurs. This is a disease of older adults (median
age, 61 years) and occurs more frequently in males (male/
female 2:1). Splenomegaly is the commonest finding on
examination, occurring in approximately two-thirds of patients.
Almost half have hepatomegaly and/or lymphadenopathy, although these are rarely bulky.5,6 Skin manifestations are not
uncommon ( 20% of patients) and include skin nodules
(Figure 1A), maculopapular rash, or, more rarely, erythroderma.
Peripheral edema, particularly periorbital and/or conjunctival
(Figure 1B), occurs relatively frequently and seems to be
particularly characteristic of T-PLL. Other features, which may
be seen at presentation or during evolution, include pleuroperitoneal effusions and CNS involvement. There is usually a marked
PB lymphocytosis, often in excess of 100 109/L with greater
than 90% of the circulating cells being prolymphocytes. Anemia
and thrombocytopenia are seen in half the cases. Lactate
dehydrogenase levels are usually elevated, but hypercalcemia,
common in HTLV-I related adult T-cell/leukemia lymphoma
(ATLL), is not a feature of T-PLL. Serology and/or DNA
analysis for HTLV I and II are consistently negative, and these
retroviruses are not implicated in the pathogenesis of the
disease.7

2012 by The American Society of Hematology

BLOOD, 19 JULY 2012 VOLUME 120, NUMBER 3

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BLOOD, 19 JULY 2012 VOLUME 120, NUMBER 3

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539

Table 1. Clinical and laboratory characteristics of T- and B-cell PLLs

Characteristic findings
Clinical features

T-PLL

B-PLL

Median age 61 y

Median age 69 y

Male:female 2:1

Male:female, 1.6:1

Splenomegaly, lymphadenopathy, skin rash, edema

B-symptoms, splenomegaly, minimal

and pleuroperitoneal effusions

lymphadenopathy, high WBC

Very high WBC

Morphology
Immunophenotype

Cytogenetics

Basophilic prolymphocytes with cytoplasmic blebs

55% prolymphocytes (usually 90%)

Small cell (20%) and SS (5%) variants

Prolymphocyte is 2 times the size of CLL lymphocyte

CD2, CD3, CD5,

SmIG strong, CD19,

CD7

CD20, CD22,

CD4/CD8 variable

CD79a,CD23 CD5

CD1a, TdT, CD25

FMC7 (CLL score 0-1)

t(14;14); inversion 14; t(X;14); iso8q; complex

13q del, 11q del, 17p del, 6qdel

TCL-1, MTCP-1, ATM

TP53, C-MYC

B-PLL, T-LGL leukemia, ATLL, SS

CLL/PL,* T-PLL, MCL (leukemic phase), SMZL, HCL-V

Median survival 7 mo with conventional therapy; 20 mo

Median survival 3 y

No t(11;14)
Oncogenes
Differential diagnosis
Prognosis

with alemtuzumab; 48 mo with alemtuzumab HSCT

T-PLL indicates T-cell prolymphocytic leukemia; T-LGL, T large granular lymphocytic leukemia; SS, Sezary syndrome; ATLL, adult T cell leukemia lymphoma; B-PLL, B-cell
prolymphocytic leukemia; CLL/PL, chronic lymphocytic leukemia with increased prolymphocytes ( 55%); HCL-V, hairy cell leukemia variant; MCL, mantle cell lymphoma;
SMZL, splenic marginal zone lymphoma; WBC, white blood cell count; and HSCT, hematopoietic stem cell transplant.
*CLL/PL 55% prolymphocytes.

Rarely, the diagnosis of T-PLL is made in a patient with a

preceding history of an inherited genetic disorder, and I have seen
patients with prior ataxia telangiectasia and Nijmegen breakage
syndrome. There are no other familial or geographic predisposing
features.

Figure 1. Clinical features of T-PLL. (A) Nodular skin infiltration. (B) Periorbital and
conjunctival edema.

Making an accurate diagnosis

Confirmation of the diagnosis requires a systematic approach and

careful integration of the results of morphology with specialized
diagnostic tests, including immunophenotyping and cytogenetics.
Morphology. Examination of the PB film is a key diagnostic
test and will often provide the first clue to the diagnosis.8
Prolymphocytes are medium-sized cells with a high nuclearcytoplasmic ratio (Figure 2). In 50% of the cases, the cells have a
round to oval nucleus; whereas in the remainder, the nuclei are
irregular, often with convolutions, although less pronounced, than
those seen in Sezary or ATLL cells. In typical T-prolymphocytes,
the nuclei have a single prominent nucleolus and intensely
basophilic agranular cytoplasm with cytoplasmic protrusions. Two
variants, small cell and cerebriform, are seen in approximately 20%
of cases. Both these variants have immunophenotypic, cytogenetic,
and clinical features, which are similar to typical T-PLL.
Morphology of other tissues (eg, BM and lymph nodes) is less
informative and may not clearly discriminate between this and
other peripheral T-cell malignancies. These tests are therefore not
essential to establish a diagnosis. Infiltration of the marrow with
prolymphocytes is with a mixed pattern (diffuse and interstitial),
and reticulin fibrosis is almost always present. Spleen histology
shows expansion of both the red and white pulp with atrophy of the
follicular centers. Infiltration of the lymph nodes is diffuse; and in
some cases, there is paracortical expansion. The skin histology is
very characteristic with dermal infiltration, preferentially around
the appendages and sparing the epidermis.
Immunophenotyping. Immunophenotyping by flow cytometry demonstrates the postthymic T-cell nature (TdT, CD1a,
CD5, CD2, CD7) of the prolymphocytes. In our Royal
Marsden Hospital series of more than 150 cases, the most common
phenotype is CD4/CD8 (60% of cases), but coexpression of
CD4/CD8 is seen in 25% (Figure 3) of cases and a minority express
CD8 alone.5,6 More than two-thirds of cases express CD3 and
TCR- in the cell membrane, whereas the remainder are negative
with either one or both markers.5 In the third of cases lacking
surface expression of CD3 and TCR-, these T cellspecific
molecules are consistently expressed in the cytoplasm and the

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540

DEARDEN

Figure 2. PB morphology from a typical case of T-PLL showing medium-sized

lymphoid cells with a regular nuclear outline, single nucleolus, and intense
basophilic cytoplasm. An occasional cell shows a cytoplasmic protrusion.

TCR- and/or chain genes are rearranged in all cases.9

T-prolymphocytes express CD7 with strong intensity in contrast to
other mature T-cell leukemias, where this marker is often weakly
positive or negative (Table 2). CD52 is expressed at high density,
explaining to some degree the in vivo sensitivity to the anti-CD52
monoclonal antibody alemtuzumab.10 Cell surface antigens linked
to T-cell activation, such as CD25, CD38, and class II HLA-DR,
may be variably expressed, but markers identifying cytotoxic
T cells, such as TIA-1, are negative, even in cases with a
CD8 phenotype11
Genetics. Recurrent chromosomal abnormalities involving
chromosome 14 are present in almost 75% of T-PLL cases, with

BLOOD, 19 JULY 2012 VOLUME 120, NUMBER 3

inversion 14 being the commonest (Figure 4A).12 Tandem translocations between the 2 chromosomes 14, t(14;14), are also present in
some cases. Both rearrangements result in activation and expression of the proto-oncogene TCL-1 (Figure 4B).13 It is also possible
to test for TCL-1 protein expression using a flow cytometry
technique, which confirms positivity in the majority of T-PLL
cases. However, assessment of TCL-1 is not routinely available,
and lack of this test result should not affect the ability to accurately
make a diagnosis or influence the choice of treatment. Another
common translocation, t(X;14) (q28;q11), seen in 20% of patients,
involves rearrangement of the TCR locus with the MTCP1 gene
(belonging to the TCL-1 gene family; Figure 4B).14 Trisomy 8 or
iso8q is seen in up to two-thirds of cases (Figure 4A).15 The C-MYC
localized at 8q24 is not rearranged in these cases, but the encoded
protein may be overexpressed. Although 11q23 abnormalities are
rarely detected on cytogenetics, molecular analysis frequently
detects abnormalities of the ATM gene. There are several other
recurrent regions of chromosomal abnormalities: loss at 22q, 13q,
6q, 9p, 12p, and 17p and gains at 22q and 6p.16,17
The combination of such distinctive clinical, morphologic,
immunophenotypic, and cytogenetic features usually means that
the diagnosis, once entertained, is very straightforward. Other than
CD52 and TCL-1 expression, none of these laboratory characteristics appears to correlate with outcome.
Differential diagnosis

T-PLL can readily be distinguished from its B-cell counterpart by

immunologic markers. Furthermore, skin infiltration and lymphadenopathy are unusual in B-PLL, although they are present in a

Figure 3. Flow cytometry in T-PLL showing negative membrane expression of CD3, strong expression of CD7 and CD5, and coexpression of CD4 and CD8. Courtesy
of Ricardo Morilla (Royal Marsden Hospital).

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BLOOD, 19 JULY 2012 VOLUME 120, NUMBER 3

LYMPHOID NEOPLASIA

541

Table 2. Differential diagnosis of mature T-cell leukemias by immunophenotype

Immunophenotype

T-PLL

T-LGL

SS

ATLL

CD2

CD3

CD7

(strong)
CD4
CD8

(in 60%)

(rarely )

(most)

(most)

Rare

Rare

Rare

Rare

(15%)
CD4/CD8 coexpression
Other antigen expression

(25%)

CD 57/CD16 (often)

Rare
CD25 in most cases

T-PLL indicates T-cell prolymphocytic leukemia; T-LGL, T-large granular lymphocytic leukemia; SS, Sezary syndrome; and ATLL, adult T-cell leukemia lymphoma.

substantial proportion of T-PLL patients. To discriminate between

T-PLL and other T-cell malignancies, including T-cell large granular
lymphocytic leukemia, ATLL, Sezary syndrome (SS), and peripheral
T-cell lymphoma (PTCL), it is crucial to integrate all the clinical

and laboratory information (PB morphology, histology, immunologic and genetic markers; Table 2). Reliance on only 1 or
2 parameters may lead to an incorrect diagnosis. For example, a
73-year-old man was referred to me with a diagnosis of refractory

Figure 4. Genetics in T-PLL. (A) Complex karyotype from a case of T-PLL showing the characteristic abnormalities of inversion 14 and trisomy 8 [gain of whole chromosome
rather than i(8q)]. The karyotype is 47,XX, 8, del12(p13.1p13.3), inv(14) (q11q32). (B) The deregulation of the oncogenes TCL-1 (chromosome 14) and MTCP-1(X chromosome)
through translocations involving the TCR alpha locus on chromosome 14. Courtesy of John Swansbury (Royal Marsden Hospital).

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542

DEARDEN

PTCL-unspecified. He had initially presented with a lymphocytosis

detected on a routine FBC. Mild splenomegaly was detected on
CT. Lymphocytes had a CD3, CD4, and CD5 (CD7 not done),
CD8 and CD25 phenotype and cytogenetics showed a complex
karyotype with inversion 14. However, the BM trephine biopsy
was reported as PTCL-unspecified. He was treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) on
which he progressed. After referral, we confirmed a diagnosis of
T-PLL; he was treated with alemtuzumab and remains in complete
remission (CR) 27 months later. The mistake here was to rely
on BM histology rather than a careful examination of the
PB morphology and a failure to integrate the results from all the
other investigations.
Of note, the term T-CLL has been used in the past (now
recognized as the small cell variant of T-PLL) but is no longer a
category recognized in the WHO classification and should be
avoided because it inaccurately suggests that T-PLL is the T-cell
equivalent of CLL. The following example illustrates how misleading this can be: a 77-year-old man was first noted to have a mild
lymphocytosis when under the urology team for treatment of a
benign bladder tumor. The film was reported as probable CLL,
but no further tests were done. At his postoperative follow-up, the
lymphocyte count was noted to have risen, immunophenotyping
was undertaken, reported as T-CLL, and 6-month follow-up was
recommended. Within a month, he presented with an acute-onset of
third, fourth, and sixth cranial nerve palsies. He was referred to
neurology where he underwent several investigations, including
lumbar puncture (but without immunophenotyping) and brain
MRI, which were inconclusive. He was treated with steroids for
assumed vasculitis without symptomatic improvement. No connection was made between his hematologic and neurologic conditions.
His white blood cells (WBCs) had also increased significantly, and
he was referred for an urgent second opinion when we were able to
make a diagnosis of T-PLL with CNS involvement. MRI showed
clear evidence of meningeal enhancement, and lumbar puncture
contained T-lymphocytes with the same aberrant phenotype as
those in the PB. He commenced treatment with intravenous
alemtuzumab and intrathecal therapy (methotrexate, cytarabine,
and hydrocortisone 6), achieving CR with complete resolution of
his neurologic impairment. He remains well and in remission
6 years later. We have had patients referred with a diagnosis of
acute lymphoblastic leukemia because of the aggressive presentation, very high WBC, and an immunophenotype negative for
membrane CD3 and with dual positivity for CD4 and CD8. I have
also seen a patient presenting with skin involvement and lymphocytosis in whom a diagnosis of T-PLL had been made, which on
careful review was revised to that of SS. Histology of the skin
biopsy was particularly helpful in this case.
What I tell patients about prognosis

There is little information regarding prognostic factors in T-PLL. In

our dataset, biologic parameters, such as immunophenoype, cytogenetics, and moleclular genetics, do not influence survival or
response to therapy. The most important predictor of outcome is
response to alemtuzumab therapy. In this regard, patients with
extramedullary disease (eg, liver, CNS, pleuroperitoneal effusions)
have lower response rate to alemtuzumab. In our series of
86 patients treated with alemtuzumab, nonresponders had a median
survival of only 4 months. In the only other large series reported
from The MD Anderson Cancer Center, 5-year survival from
diagnosis was 21% and poorer outcome was associated with high
WBC, short lymphocyte doubling time, older age, and high

BLOOD, 19 JULY 2012 VOLUME 120, NUMBER 3

Figure 5. Treatment algorithm for T-PLL.

expression of TCL-1 protein measured by flow cytometry and

immunohistochemistry.18 Patients will often be aware from their
reading of the literature that this is an aggressive leukemia with
poor OS. However, this information is largely based on retrospective data, and the outlook has improved with the introduction of
newer treatment approaches. Even in some of my older patients
(older than 80 years), survival has exceeded 5 years after singleagent alemtuzumab; and in some younger patients who have
undergone HSCT, remissions have exceeded 10 years. In the future,
there is some hope that survival will improve further with the
availability of additional effective therapies.

How I treat T-PLL

How I manage indolent T-PLL

In those patients presenting with an asymptomatic lymphocytosis

that is relatively stable or only slowly progressive, I am happy to
monitor until evidence of disease progression. However, the
progression may occur rapidly, and I therefore monitor these
patients more closely than I would a patient with stage A CLL. This
will often allow time to identify a suitable donor if allogeneic
transplant is planned so that there will be no delays once treatment
with alemtuzumab is initiated. The duration of an indolent phase is
variable, but it is unusual for it to persist for more than 1 to 2 years.
How I treat patients requiring first therapy

More typically, patients with T-PLL present with an aggressive

clinical picture, and the disease is usually resistant to conventional
chemotherapy and can be rapidly fatal. Currently, the best treatment is alemtuzumab followed by consolidation with a stem cell
transplant where possible. This approach has led to an extension of
the median survival from 7 months in our historic series of more
than 70 patients treated with conventional chemotherapy to more
than 4 years for those patients receiving alemtuzumab followed by
HSCT. I follow the algorithm in Figure 5.
Alemtuzumab (Campath-1H) is a humanized IgG1 antibody,
which targets the CD52 antigen that is highly expressed on normal
and malignant T- and B-lymphocytes and monocytes but not on
hemopoietic stem cells.19 The CD52 antigen is expressed at
particularly high density on T-PLL cells10 The mechanism of action
of alemtuzumab in vivo is not fully elucidated, but in vitro the

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BLOOD, 19 JULY 2012 VOLUME 120, NUMBER 3

LYMPHOID NEOPLASIA

Table 3. Treatment of T-PLL comparing patients treated first line,

either with IV or SC alemtuzumab, with those treated with relapsed
or refractory disease (N 86)22
First-line IV

First-line SC

Relapsed/refractory IV

No. of patients

32

45

ORR, %

91

33*

74

CR, %

81

33*

60

PFS at 12 mo, %

67

67

26

HSCT, %

50

55

30

OS at 48 mo, %

37

33

18

IV indicates intravenous; SC, subcutaneous; CR, complete remission; PR, partial

remission; ORR, overall response rate; PFS, progression-free survival; HSCT,
hematopoietic stem cell transplant; and OS, overall survival.
*Increased to 67% when changed to IV and/or pentostatin added, but 2 of
9 patients died while on treatment.

antibody can induce cell death by antibody-dependent cellular

cytotoxicity, complement activation, and possibly also through
direct apoptosis. We have previously reported the results of a study
using intravenous alemtuzumab at the standard dose of 30 mg
3 times a week until maximal response in 39 previously treated
relapsed/refractory patients, which showed 60% CR and 16%
partial remission (PR).20,21 Median disease-free interval after
therapy was 7 months (range, 4-45 months). Longer follow-up of
this series shows a median survival of 2 years for those patients
achieving a CR and 9 months for those in PR. We have now treated
a total of 86 T-PLL patients with single-agent alemtuzumab
(Table 3): 45 previously treated patients and 41 who were
therapy-naive. Nine of the patients treated first-line were enrolled
on a pilot study to evaluate the subcutaneous route of administration of alemtuzumab.22 Although data from CLL suggest that
subcutaneous alemtuzumab has equal efficacy compared with
intravenous administration, we found that this was not the case in
T-PLL. The pilot study was terminated early because of the
dramatic decrease in response rates associated with the change to
subcutaneous administration. Intravenous alemtuzumab results in
overall response rates (ORR) in excess of 90% with 81% CRs when
given to previously untreated patients with T-PLL (Table 3).22 The
ORR fell to only 33% when the antibody was administered
subcutaneously. It was possible to rescue a proportion of these
patients by switching to intravenous administration and/or adding
pentostatin, but 2 of 9 patients died on treatment. The probable
reason for this poor result is the longer delay in achieving peak
antibody levels via the subcutaneous route,23,24 which may be
critical in this rapidly progressive leukemia. Alternatively, the poor
result may be because subcutaneous administration in a previously
untreated patient could be sufficiently immunogenic to induce
neutralizing antibodies. This is the only study that has examined the
use of subcutaneous alemtuzumab, but the effects were so striking
that, on the basis of these results, I always use intravenous
administration of alemtuzumab in patients with T-PLL.
Skin disease responds very well to alemtuzumab therapy, and
there is also experience of good efficacy of single-agent alemtuzumab in SS. However, for patients with CNS disease, it is
necessary to administer CNS-directed therapy, either triple (methotrexate 12.5 mg, cytarabine 50 mg, and hydrocortisone 12.5 mg)
intrathecal, or high-dose systemic methotrexate (3 g intravenous)
depending on the distribution of disease. We do not use routine
CNS prophylaxis.
We have found alemtuzumab to be well tolerated in this patient
population with fewer infectious complications than when it is used
in the relapsed CLL patient group ( 10% in T-PLL vs 40% in CLL
in our institution). Careful attention to infection prophylaxis for

543

Pneumocystis jerovicci and herpes viruses together with regular

monitoring for CMV reactivation have minimized serious infections. Infusion reactions are common on initiating intravenous
therapy but can be readily controlled with the use of premedication
and rarely last beyond the first week of treatment. None of our
patients has developed tumor lysis.
Thus, alemtuzumab administered intravenously as a single
agent will induce remissions in the majority of patients treated
first-line, with minimal toxicity. Remarkably, these responses occur
regardless of the apparent bulk of the disease at presentation (ie,
high WBC, lactate dehydrogenase, and splenomegaly). It is not
advisable to use a debulking strategy using steroids or multiagent
regimens, such as CHOP, because this is usually ineffective, delays
starting more effective antibody therapy, and adds substantially
to toxicity.
How I manage slow responders

Treatment failures are in a minority. In those patients where there is

a high tumor bulk and the WBC remains elevated 3 weeks or more
after initiating treatment, it is reasonable to increase the frequency
of alemtuzumab administration to daily (to more quickly saturate
the binding sites) and/or to add pentostatin at a dose of 4 mg/m2
once a week for 4 weeks followed by every 2 weeks in responding
patients to best response or to a maximum of 12 weeks. Administration of this dose of pentostatin is dependent on adequate renal
function. Pentostatin causes more myelosuppresssion than alemtuzumab used alone and is also associated with nausea, which may
last up to 72 hours after administration of the dose. The choice of
pentostatin is based on our prior experience with this as a single
agent.25 The addition of an alternative purine analog or a novel
therapy may provide equivalent or superior disease control, but
currently the data on combination regimens are limited. Extramedullary disease, such as serous effusions and liver involvement,
more often predict for resistance to alemtuzumab monotherapy, but
this can frequently be overcome by the addition of a purine analog,
such as pentostatin.
Who should have an HSCT

The main challenge as a clinician treating T-PLL is to deliver

long-term disease-free survival. Although some responses with
alemtuzumab are very prolonged ( 5 years) longer-term follow-up
on patients treated with alemtuzumab in our series suggests that all
patients do eventually relapse21 (Figure 6). Experience with both
autologous and allogeneic HSCT, although limited, is
encouraging.26-32 Single case reports and small series are often
misleading because of patient selection bias, and there are only
3 larger reports of hematopoietic stem cell transplantation (HSCT)
in the literature. Nevertheless, our experience suggests that consolidation with an HSCT in first or subsequent remission offers
potential advantages to patients. We have recently reviewed data on
28 T-PLL patients treated on a common protocol with alemtuzumab
followed by either autologous (15) or allogeneic (13) transplantation (Table 4).31 We compared clinical outcomes to 23 retrospectively selected patients who had achieved a CR after alemtuzumab
treatment and survived at least 6 months but had not undergone a
transplant (non-HSCT group). Apart from age (median 64 years in
the non-HSCT group vs 58 years for autograft and 51 years for
allograft), the clinical and disease characteristics of the retrospective cohort were the same as those of the patients undergoing
HSCT. OS was similar in the autograft and allograft groups at a
median of 48 months compared with a median survival for the

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544

BLOOD, 19 JULY 2012 VOLUME 120, NUMBER 3

DEARDEN

those patients who are also ineligible for autologous HSCT, we

need to explore other strategies.
Minimal residual disease can be monitored by flow cytometry
(aberrant phenotype) or PCR, but as yet there is no evidence that
this helps in disease management. All nonallografted patients
progress, so the presence of residual disease does not necessarily
help to define a higher risk group. Minimal residual disease
monitoring has not been explored in the transplant setting but may
be more useful here in directing DLI.
Alternative first-line treatments

Figure 6. Survival curve for 86 T-PLL patients treated with alemtuzumab.

Survivors beyond 72 months are those who received consolidation with a HSCT.

non-HSCT group of 20 months (Table 4). There was no association

between age and survival in either group. We have not seen any
failure of engraftment despite the prior use of alemtuzumab,
although we usually ensure at least a 3-month period between
completing induction treatment and the allo-HSCT. There has been
a retrospective review of the European Group for Blood and
Marrow Transplantation database with 41 T-PLL patients identified
who have undergone an allogeneic HSCT.32 Three-year progressionfree survival (PFS) and OS were 19% and 21%, respectively. The
3 year nonrelapse mortality and relapse rate were each 41%, with
the majority of relapses occurring in the first year. The main
difference between this group of patients and our own allo-HSCT
series was the proportion of patients in CR at the time of transplant
(11 of 41 for European Group for Blood and Marrow Transplantation series vs 10 of 13 for Royal Marsden Hospital series). In
multivariate analysis, factors associated with longer PFS were the
use of total body irradiation in the conditioning regimen and a
shorter interval between diagnosis and HSCT.
We therefore think that HSCT after alemtuzumab may provide
benefit over alemtuzumab alone and is associated with long-term
survival ( 5 years) for some patients. The introduction of
reduced-intensity conditioning has minimized the transplantrelated mortality, and it is hoped that, after longer follow-up, this
will translate into improved survival for the allograft group. Of our
series of more than 80 patients, almost half of those achieving
remission have proceeded to either autologous or allogeneic HSCT
(Table 3). One of our patients who only achieved a PR after
alemtuzumab received an reduced-intensity conditioning, unrelated donor transplant, and remains in CR more than 10 years later,
suggesting that this approach has curative potential. Nevertheless,
allografted patients do still have a risk of relapse; and so far,
outcome after relapse in our experience has been very poor with no
clarity regarding the best relapse treatment or the benefit of DLI.
There remains therefore some uncertainty about the optimal
strategy for allogeneic HSCT, which would be best addressed by
conducting prospective clinical trials that are currently not available. In the absence of such robust data but in the knowledge that
allograft may currently provide the only possibility of cure in this
disease, I do continue to offer this to all suitable patients in first
remission. Allografts, however, are an option only in a proportion
(30%-50%) of patients with T-PLL. Autologous HSCT is also a
benefit for patients, prolonging remissions with much less treatmentrelated toxicity than allogeneic HSCT, but not resulting in cure. For

The rarity of T-PLL has meant that there have been no prospective
randomized controlled studies to compare the efficacy of different
therapies. Indeed, even nonrandomized studies are mostly retrospective with small patient numbers accrued over prolonged periods of
time (Table 5). Entering patients into clinical trials is to be
encouraged. However, currently there are no prospective front-line
studies open.
Historically, patients were treated with alkylating agents, such
as chlorambucil, or combinations, such as CHOP, with only a
minority ( 30%) of short-lived responses (3 months) and a dismal
median survival of only 7 months.5 This approach should therefore
be avoided because of lack of efficacy.
The advent of purine analogs, such as pentostatin, fludarabine,
and cladribine (2CDA), improved response rates and in some cases
induced a durable remission enabling the patient to undergo a
stem cell transplant. In our Royal Marsden Hospital series of
56 predominately relapsed/refractory T-PLL patients treated with
pentostatin, the ORR was 45% with 9% achieving CR.25 Median
duration of response was only 6 months, but survival was improved
for responders compared with historical controls.
The successful use of chemoimmunotherapy in B-cell malignancies prompted similar studies in T-PLL. The German CLL study
group have conducted a prospective phase 2 trial in 25 patients with
previously treated (9) and treatment-naive (16) T-PLL.33 The
sequential therapy composed up to 4 cycles of fludarabine,
mitoxantrone, and cyclophosphamide (FMC) given every 4 weeks
followed by consolidation with intravenous alemtuzumab 3 times a
week in responding patients, one to 3 months after completion of
chemotherapy. ORR was 68% after FMC (6CR) and 92% after both
therapies. Alemtuzumab consolidation in 21 patients increased the
ORR to 95% in these patients (80% of all the trial patients) with a
doubling of the CR rate (12 CR). Median OS and PFS were 17 and
12 months, respectively. The MD Anderson Cancer Center has
explored the use of alemtuzumab in combination with pentostatin
in a range of PTCL, including T-PLL, and found activity (ORR,
Table 4. Outcomes for patients with T-PLL treated with
alemtuzumab alone or followed by autologous or allogeneic HSCT31

No. of cases
Median age, y (range)
Males:females

Autograft

Allograft

All HSCT

15

13

28

Controls*
23

58 (43-68)

51 (39-61)

55 (39-68)

64 (35-81)

8:7

10:3

18:10

16:7

TRM rate, %

31

18

NA

Relapse rate, %

60

33

48

96

Median DFS, mo

28

24

24

10

Median OS, mo

52

33

48

20

2-y OS rate, %

78

62

71

31

5-y OS rate, %

40

33

34

HSCT indicates hematopoietic stem cell transplant; TRM, transplant-related

mortality; OS, overall survival; NA, not applicable; and DFS, disease-free survival.
*Control group: patients who achieved CR and survived at least 6 months.

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545

Table 5. Summary of treatment trials in T-PLL

Study

Regimen

No.

CR, %

ORR, %

Medial PFS, mo

Median OS, mo

Mercieca25

Pentostatin*

55 pretreated

45

Dearden21

Alemtuzumab (IV)

39 pretreated

60

76

10

Keating35

Alemtuzumab (IV)*

76 pretreated

38

50

4.5

7.5

Dearden22

Alemtuzumab (IV)

32 previously untreated

81

91

67% at 1 y

37% at 4 y

11.5

17.1

7.8

10.2

Hopfinger33

FMC, then

9 pretreated

24 (FMC)

Total 92

Alemtuzumab (IV)

16 previously untreated

48 (alemtuzumab)

17/25 68% after FMC

Pentostatin alemtuzumab (IV)

13 (treated untreated)

62

20/21 95% after alemtuzumab

Ravandi34

69

CR indicates complete remission; ORR, overall response rate; MPFS, median progression-free survival; and MS, median overall survival.
*Retrospective analysis.
Compassionate-use trial.

69%) similar to that seen with alemtuzumab alone.34 These

treatment trials are summarized in Table 5.
However, given the comparable results with single-agent alemtuzumab, I do not think that any of the aforementioned combination
strategies offer convincing additional benefit while adding substantially to toxicity. I reserve the addition of a purine analog for those
patients failing to respond optimally to antibody treatment alone.
How I treat relapsed refractory T-PLL

Despite the very high RR with alemtuzumab, relapse is inevitable

for all but the minority of patients who appear cured after
allogeneic HSCT. Although improved, median survival remains
only 20 months (Figure 6). For those patients who have not
previously received alemtuzumab, this is the treatment of choice at
relapse and good RRs have been documented in the relapsed/
refractory (alemtuzumab-naive) patient group.20,21,35 For those
patients who received induction therapy with alemtuzumab, with
response duration of at least 6 months, retreatment can be
successful in achieving a second, or even third, remission ( 50%
of patients will respond a second time), but this is usually of much
shorter duration. Occasionally, the T-PLL cells lose expression of
the CD52 antigen precluding further use of alemtuzumab.36
I therefore always retest for this at relapse. Maintenance alemtuzumab has not been formally evaluated and is likely to encourage
early loss of CD52 expression. For those patients who fail or are
unsuitable for alemtuzumab retreatment, I usually use a purine
analog-based therapy, but response rates are not high. Nelarabine,
with or without fludarabine, is an alternative for which there is
some evidence of activity in T-PLL.37 In a phase 1 study in
11 T-PLL patients, ORR was 20% for nelarabine alone, rising to
63% (13% CR) for the combination with fludarabine. If the patient
is a suitable candidate for an allogeneic transplant, then it is
sometimes possible to induce a remission with an intensive
combination regimen and proceed directly to HSCT. With current
treatment options, very few patients will have a successful outcome
after relapse.
How an understanding of the biology can help in the
development of new treatment strategies

Most patients with T-PLL will still die from their disease, and new
therapies are badly needed. Knowledge of the disrupted pathways
and mechanisms underlying activation and proliferation in T-PLL
has raised the possibility of developing a treatment approach that
targets these growth and survival signals by the use of smallmolecule inhibitors. Potential targets include the following:
ATM. ATM, frequently mutated in T-PLL,38-40 results in
impaired DNA double-strand break repair and renders the cell
particularly sensitive to poly-ADP-ribose polymerase inhibition.41

Trials are ongoing using oral poly-ADP-ribose polymerase inhibitors in the treatment of relapsed T-PLL.
AKT and TCL-1. The TCL-1 family oncoproteins augment
AKT activation by forming stable complexes at the cell membrane,
which allow enhanced signal transduction, cell proliferation, and
survival.42 The majority of T-PLL cases have overexpression of
TCL-1 and, in a smaller number of cases, of MTCP-1. Potentially,
inhibition of AKT prevents its recruitment to the cell membrane
and subsequent activation through phosphorylation. This would
then have downstream effects on effector functions. Similarly,
direct blockade of TCL-1, acting independently or in concert with
AKT inhibition, may abrogate the clonal expansion driven by
dysregulation of this pathway.
Telomerase. Extremely short telomeres and high levels of
telomerase activity have been reported in T-PLL, and T-PLL cells
are sensitive to telomerase inhibition in vitro.43
Other therapeutic targets. Other intracellular signaling pathways, such as JAK-STAT and IRF, also offer potential targets for
inhibition. In addition, there is the possibility of epigenetic
modification, with evidence that combinations which include
epigenetic drugs can help overcome resistance to alemtuzumab,
which has arisen through down-regulation of CD52. The use of
high-density genomic mapping and whole-genome sequencing is
likely to identify further candidate genes, leading to a better
understanding of pathogenesis in T-PLL and a more directed
approach to therapy.44-46

How I manage B-PLL

B-PLL is a very rare mature B-cell malignancy with an aggressive
clinical course, refractoriness to chemotherapy, and a median
survival of 3 years. In the early 1970s, B-PLL was initially
described as a variant form of B-cell CLL.47 However, in the WHO
classification, it is included as a distinct clinicopathologic entity
and defined as a malignancy of prolymphocytes affecting the
blood, BM, and spleen.3 B-PLL should be distinguished from CLL
with increased prolymphocytes (CLL/PL). A small proportion of
patients with CLL undergo prolymphocytoid transformation, and
PB morphology reveals the presence of a mixture of small mature
CLL cells and prolymphocytes in contrast to typical B-PLL where
the circulating cells are monomorphic prolymphocytes.
How I recognize the clinical features of B-PLL

This is another leukemia that predominantly affects older people

and the median age at presentation of 69 years is close to that of
CLL and older than that of T-PLL (Table 1).6 There is only a slight

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546

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BLOOD, 19 JULY 2012 VOLUME 120, NUMBER 3

Figure 7. PB morphology of 4 different B-cell leukemias. (A) B-PLL, showing monomorphic prolymphocytes (PL) with condensed chromatin, prominent nucleolus, and
scanty basophilic cytoplasm. (B) CLL/PL showing a single prolymphocyte (PL), and several typical CLL cells, which are half the size of the PL, have less cytoplasm and no
nucleolus. (C) HCL-V showing cells with condensed chromatin and a conspicuous single nucleolus, but with more abundant pale cytoplasm with cytoplasmic projections.
(D) SMZL showing lymphocytes with short polar villi and basophilic cytoplasm.

male preponderance, however. Patients often present with advanced disease: B-symptoms, massive splenomegaly, absent or
minimal lymphadenopathy, and high WBC count. As in T-PLL, a
small proportion of patients have an indolent asymptomatic phase
with frank progressive disease within a few months or years. Our
experience in 60 cases shows that splenomegaly is the most
common feature, but up to one-third of patients have, or develop,
small-volume lymphadenopathy.6 However, serous effusions or
CNS involvement are rare, and skin involvement, in contrast to
T-PLL, is not seen.
How I diagnose B-PLL

True B-PLL is extremely rare, accounting for only approximately

1% of lymphocytic leukemias, and its existence as a separate entity
has been debated. The diagnosis is much more challenging than
that of the T-cell counterpart because of the considerable overlap
with other mature B-cell leukemias and lymphomas, such as mantle
cell lymphoma (MCL) or splenic marginal zone lymphoma (SMZL).
It is possible that, with the advent of more precise diagnostic tools,
it will be possible to attribute cases currently identified as B-PLL to
other disease categories.
Morphology. Careful examination of PB morphology is key to
an accurate diagnosis of B-PLL. The prolymphocyte count must be
greater than 55% in the PB and usually exceeds 90%. The
B-prolymphocyte has a characteristic large size, twice that of a
small CLL lymphocyte (Figure 7A). The nuclear chromatin is
moderately condensed, there is often a prominent central nucleolus,

and the nuclear outline is typically round and more uniform than in
CLL or CLL/PLL (Figure 7B). The cytoplasm is more abundant
than in CLL, clear, and only weakly basophilic. In contrast to the
rarer variant form of hairy cell leukemia (HCL-V; Figure 7C) and
the circulating cells in SMZL (Figure 7D), the cytoplasm generally
has a smooth outline. BM trephine biopsies are usually required as
they provide important diagnostic information. The infiltrate is
interstitial and nodular with an intertrabecular distribution. In
contrast to CLL, proliferation centers are not seen. Lymph node or
spleen histology is rarely necessary to distinguish between B-PLL
and CLL but may be helpful if a diagnosis of MCL or other
splenic lymphomas is considered. In B-PLL, spleen histology
shows expanded white pulp nodules and red pulp infiltration with
cells of the same morphology as seen in the PB (Figure 8A). The
central nucleolus is often very marked in H&E-stained sections
(Figure 8B).
Immunophenotype. The presence of a monoclonal B-cell
proliferation is confirmed by establishing light chain restriction and
the B cells further characterized by use of a panel of immunophenotypic reagents. Importantly, this will rule out the presence of typical
CLL (CD5, CD23, surface immunoglobulinweak, FMC7,
CD79bweak) or CLL/PLL, which has the same phenotype (Table 6).
We use this panel of markers to construct a CLL score.48 Whereas
high scores of 4 or 5 are expected in CLL, lower scores of 0 to
1, and rarely 2, are seen in B-PLL. Low scores are also seen in other
B-cell leukemias and lymphomas. The cells in B-PLL express
various pan B-cell antigens with strong intensity (CD20, CD22,

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547

cyclin D1.55 It is negative in most other mature B-cell malignancies

tested, but expression can be seen, independent of t(11,14), in up to
50% of cases of HCL and Burkitt lymphoma.56
We have documented mutations of the TP53 gene in more than
50% of the B-PLL cases. This incidence is the highest reported
among all the subtypes of B-cell malignancies and is likely to be
responsible for the frequent resistance to therapy seen in this
disease.57 Approximately half of B-PLL cases have unmutated
immunoglobulin heavy chain variable region genes, with usage of
V3-23 and V4-34 in one-third of the cases.49 The immunoglobulin
heavy chain variable gene usage is different from that of CLL. The
majority of TP53 deleted cases are unmutated.
Gene expression profiling demonstrated that B-PLL has a
signature quite distinct from that of CLL or CLL/PL.58 Approximately 6000 genes are differentially expressed between CLL and
B-PLL, with 75% of these genes showing a greater than 2-fold
change in expression. Most overexpressed genes in B-PLL were
those involved in cell proliferation/cell cycle, including C-MYC.
Chromosomal translocations involving 8q24 [eg, t(8;14)] have
been reported in cases of B-PLL, suggesting that C-MYC alterations may be important in the pathogenesis of a subset of
these cases.59,60
The above evidence from genetic analysis supports the view
that B-PLL is a separate entity, at least in relation to CLL. It is also
possible that some of these differences are simply a result of
misclassification. As yet, there is insufficient evidence regarding
where B-PLL sits in relation to other splenomegalic lymphoproliferative disorders, such as SMZL and HCL-V, in relation to genetic
profiling. The cell of origin of these disorders is poorly characterized, and further studies are needed to clarify the relationships
between them.
Figure 8. Histology of the spleen in B-PLL. (A) Low power view (original
magnification 20) showing replacement of the white pulp and infiltration of the red
pulp. (B) High power view (original magnification 100) of the white pulp showing the
typical prolymphocyte morphology with abundant cytoplasm, round nuclei, and a
central eosinophilic nucleolus. Courtesy of Andrew Wotherspoon (Royal Marsden
Hospital)

CD24, CD79b, and FMC 7), and surface immunoglobulin (IgM or

IgM/IgD) is detected at much higher levels than in CLL. The
expression of markers, such as FMC7 and CD11c, suggests that the
cells are at a late stage of maturation. Most cases of B-PLL are
CD23 and CD5, although up to 30% may be CD5 and these
cases may be difficult to differentiate from MCL in leukemic phase.
In a small number of cases tested, approximately 50% had positive
expression of ZAP 70 and CD38, but this did not have a prognostic
impact.49
Genetics. Only a few cytogenetic studies have been reported in
B-PLL because of the rarity of the disease and the difficulty of
obtaining prolymphocytes in metaphase.50-53 Use of B-cell mitogens might increase the detection rate of cytogenetic changes.
Complex karyotypic changes are common. Using interphase FISH,
13q14 deletions, 17p deletions, and monoallelic 11q23 deletions
can be identified, but trisomy 12 is rare.51 Other abnormalities
described include 6q, t(6;12), and structural aberrations of 1p and
1q.50 Although t(11;14) has previously been described in B-PLL, it
is clear now that these cases represent a leukemic phase of MCL,
for which this is the hallmark translocation.54 This also highlights
the importance of tissue-staining for cyclin D1 and SOX11 in such
cases, as PB morphology and immunophenotyping is not always
discriminatory. SOX 11 has high sensitivity for MCL, being
positive in more than 90% of cases, including those negative for

Differential diagnosis

The differential diagnosis of B-PLL is with CLL/PL, leukemic

MCL, HCL-V, SMZL, and T-PLL. Immunophenotyping will
readily distinguish B-cell from T-cell PLL, even when the clinical
presentation and PB morphology are the same. The percentage of
PLs, the CLL score, and the presence of proliferation centers in the
BM biopsy help to define CLL with an increase in prolymphocytes.
True de novo B-PLL does not arise on a background of known
CLL. However, there is considerable overlap between the features
of B-PLL and several other mature B-cell malignancies with
PB involvement, which can make the diagnosis difficult. Integration of the clinical picture with results from morphology, histology,
immunophenotype, and genetics, as outlined in the sections above
and summarized in Table 6, usually allows separation of these
disorders (Figures 7 and 8). The demonstration of t(11;14) and
positive expression of cyclin D1 and/or SOX 11 is able to identify
cases of MCL with a leukemic presentation. In my experience, the
greatest difficulty is with SMZL and HCL-V where the similar
clinical presentation (older age, splenomegaly, and lymphocytosis),
the overlap in morphologic features (cytoplasmic basophilia,
nucleolus in HCL-V, and the loss of the fine hairy projections in
poorly prepared blood films from HCL-V and SMZL), together
with a lack of distinct immunophenotypic or cytogenetic markers,
can make precise diagnosis problematic. Spleen histology, when
available, can be helpful61 (Figure 8). The presence of B symptoms,
very high WBC ( 100 109/L), and aggressive clinical course
are much more characteristic of B-PLL than of SMZL or HCL-V.
The distinction is important therapeutically because many cases of
HCL-V and SMZL do not require therapy or may benefit from

69

70

(Figure 7B)

cytoplasmic outline

Weak (IgM/IgD)
CD10

Strong (IgM)

CD10

rarely C-MYC

12

some proliferation centers

White and red pulp involvement;

centers

Nodular/interstitial proliferation

atrophic white pulp

Expanded diffuse red pulp with blood lakes,

Intrasinusoidal; no increased reticulin

increase

with atrophic white pulp

rarer red pulp lymphoma

with expansion of white pulp;

Infiltration of red and white pulp

Nodular/intrasinusoidal

Del 7q, trisomy 3, trisomy 18

cyclin D1

CD103, CD123-annexin 1,

Strong (IgMIgD)

(usually)

30% (weak)

cytoplasm (Figure 7D)

Short polar villi; basophilic

cell variants

Mantle zone; blastoid and small

Cells with irregular nuclei

t (11;14)

BCL2

Cyclin D1 SOX 11 ,

Strong (IgM/IgD)

(most)

indentation common

irregular nucleus clefting or

Heterogeneous; larger size;

Usually 50 109/L

3-5

2:1

60

MCL

B-PLL indicates B-cell prolymphocytic leukemia; CLL/PL, mixed cellularity chronic lymphocytic leukemia with increased prolymphocytes; HCL, hairy cell leukemia; SMZL, splenic marginal zone lymphoma (including splenic diffuse red pulp
lymphoma); and MCL, mantle cell lymphoma.

by prolymphocytes

White and red pulp infiltration

proliferation centers

Nodular/interstitial; no

No consistent changes

TRAP, annexin 1 (unlike typical HCL)

CD11c , CD103 , CD25, CD123,

Strong (IgG)

(Figure 7C)

nuclei, hairy cytoplasmic projections

Prominent nucleolus, occasional bilobed

12
Usually normal or low level

1:1

62

SMZL

Modest, 20-40 109/L. No monocytopenia

1.6:1

71

HCL variant

DEARDEN

Spleen histology

BM histology

Cytogenetics

Other antigens
Del 13q, 11q, and 17p; trisomy

( most)

CD23

CD5

Del 11q, del, 13q, del17p,

(weak)

SmIg

(weak)

(strong)

CD22

(Figure 7A)

and account for 55%

PLs twice the size of CLL cells

round nucleus, regular

Prominent single nucleolus;

3-7
Variable

2:1

High, 100 109/L

1.6:1

CLL/PL

CD79b

Immunophenotype

PB morphology

Lymphocyte count

Median OS, y

Male/female ratio

Median age, y

B-PLL

548

Table 6. Differential diagnosis of mature B-cell leukemias/lymphomas by clinical and laboratory parameters

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BLOOD, 19 JULY 2012 VOLUME 120, NUMBER 3

Figure 9. Treatment algorithm for B-PLL.

splenectomy or rituximab monotherapy alone, whereas B-PLL is

likely to require a combination chemo-immunotherapy approach.
Prognosis

B-PLL is generally regarded as having a poor prognosis, with

historical data suggesting a median OS of approximately 3 years.
None of the markers associated with poor prognosis in CLL, other
than the presence of TP53 deletions/mutations, appears to influence
outcome, although the data are very limited. Furthermore, very
little information is available from prospective series in the era of
antibody therapy which, as in CLL, may have resulted in significant
improvement in survival. The only clear marker of poor outcome
remains the presence of TP53 abnormalities, and I would use this,
in particular, to influence patient selection for HSCT approaches.
How I treat B-PLL

B-PLL is not only difficult to diagnose but is often difficult to treat.

Despite the differences in biology and clinical features, I usually
adopt a similar treatment approach as I would to a patient with
CLL, after the algorithm in Figure 9. The clinical course is variable
and therapy is not indicated in asymptomatic patients.62 However,
B-PLL rarely remains indolent for long, in contrast to stage A CLL.
Alkylating agents, such as chlorambucil, are of little value in the
management of B-PLL. Combination regimens, such as cyclophosphamide, doxorubicin, oncovin, and prednisolone (CHOP), have
recorded responses (partial responses and rare CRs) in up to
one-third of cases.63 Single-agent purine analogs, such as fludarabine, cladribine, and pentostatin, may achieve responses in 50% of
patients, including a minority of CRs, but with few lasting more
than 12 months.64,65 There are few data on the use of purine analog
combinations in B-PLL.66,67 A phase 2 trial using fludarabine and
cyclophosphomide showed an ORR of 50% with a median survival
of 32 months.66 There are case reports documenting the successful
treatment of B-PLL with the anti-CD20 monoclonal antibody
rituximab.68 Combinations of fludarabine or bendamustine with
mitoxantrone or epirubicin and rituximab (FMR, FER, and BMR)
have also been reported to have activity in B-PLL.69-71 Given the
excellent responses seen in CLL and MCL with the combination of
fludarabine, cyclophosphomide, and rituximab, my usual approach
to fit patients without TP53 abnormalities is to use this regimen as
first-line therapy. In my experience, this has induced durable CRs
in excess of 5 years. Because bendamustine plus rituximab has
been shown to have efficacy in CLL and other B-cell malignancies,

LYMPHOID NEOPLASIA

549

this could also be a very suitable therapy and may be associated

with less hematologic toxicity.
Alemtuzumab also has potential in B-PLL.72,73 As in CLL,
B-PLL patients with TP53 deletions or mutations should be treated
with alemtuzumab because this abnormality is associated with
primary resistance to purine analog-based therapy. Alemtuzumab is
also most active in the blood, BM, and spleen, which are the main
sites involved in B-PLL, whereas bulky lymphadenopathy is
almost never seen. We have previously reported a CR in a patient
with B-PLL after subcutaneous alemtuzumab 3 times a week for
12 weeks.73
Patients presenting with massive splenomegaly and who are not
considered fit for systemic treatment or are refractory to chemotherapy may be effectively palliated with splenectomy or splenic
irradiation. Not only does splenectomy remove a major proliferative focus and considerable tumor bulk in this disease, but it can
also relieve hypersplenism and facilitate further treatment. In frail
patients, splenectomy may not be feasible and splenic irradiation
may be a suitable alternative.74
Stem cell transplantation should also be considered in younger,
fit patients who have responded to their initial therapy, as disease
progression is inevitable. Allogeneic HSCT gives patients the
possibility of a long-term cure by potentially harnessing a graftversus-leukemia effect.29,75 However, the morbidity and mortality
associated with this procedure are significant, and often it is not a
feasible option because of patient age or comorbidities. However,
the introduction of nonmyeloablative approaches has widened the
eligibility, making this available as a treatment option in a larger
cohort of patients.
In conclusion, T-PLL and B-PLL are 2 rare clinically aggressive
but distinct disease entities with characteristic morphologic, immunophenotypic, and molecular features.
Therapeutic options for T-PLL have improved with the use of
alemtuzumab monoclonal antibody therapy, delivered intravenously, with the majority of patients now achieving durable
remissions. However, this treatment is not curative, and remission
should be consolidated with stem cell transplant in suitable patients.
Rituximab-based chemo-immunotherapy combinations should be considered as first-line therapy for B-PLL with alemtuzumab used for those
presenting with abnormalities of TP53. Splenectomy or splenic irradiation may still have a role, especially as palliation. Eligible patients
should also be considered for HSCT procedures.

Acknowledgments
The author thanks all her colleagues at the Royal Marsden Hospital
and the Institute of Cancer Research, especially Monica Else for
data analysis and reviewing the manuscript, Alison and Ricardo
Morilla (Figures 3 and 7), John Swansbury (Figure 4A), Andrew
Wotherspoon (Figure 8), and Saman Hewamana, Estella Matutes,
Mark Ethell, Bronwen Shaw, Mike Potter, and Daniel Catovsky as well
as all the collaborators in clinical studies. Most of her gratitude goes to
all the patients she has had the privilege to treat, and who, through their
willingness to participate in clinical and laboratory research, have given
her the opportunity to learn more about these diseases.

Authorship
Contribution: C.D. wrote the manuscript.

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550

BLOOD, 19 JULY 2012 VOLUME 120, NUMBER 3

DEARDEN

Conflict-of-interest disclosure: C.D. has received honoraria

from Genzyme, Bayer Schering Pharma, and Roche.
Correspondence: Claire Dearden, Department of Haemato-

Oncology, Royal Marsden Hospital, Downs Road, Sutton,

Surrey SM2 5PT, United Kingdom; e-mail: claire.dearden@
rmh.nhs.uk.

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